One of the most significant health problems is an inadequate control of pain, especially chronic pain associated with diseases such as cancer, back pain, arthritis, and diabetic neuropathy. It is estimated that the annual cost for health care and lost productivity related to pain is over $100 billion in the U.S. One survey reported that nearly one-third of the U.S. population experiences chronic pain at some point in life. The impact of pain on society is measured not only in economic numbers, but, more importantly, by suffering. For example, more than 50 million Americans are partially or totally disabled by chronic pain, which accounts for about one-fourth of all workdays lost annually.
Analgesics are agents that relieve pain by acting centrally to elevate pain threshold, preferably without disturbing consciousness or altering other sensory functions. A mechanism by which analgesic drugs obtund pain (i.e., raise the pain threshold) has been formulated. Research in this area has resulted in the development of a number of opiate and opioid analgesics having diverse pharmacological actions. While opioid analgesics remain the mainstay for pain treatment, prolonged use of these drugs leads to tolerance that results in frequent dose escalation and increased side effects, such as altered cognitive state.
Opioid analgesics remain the preferred therapy for the treatment of moderate to severe pain, and of many painful chronic diseases. However, the chronic use of opioid drugs produces tolerance to these drugs. Whereas tolerance develops to essentially all opioid effects at varying rates, an attenuated analgesic effect is the most devastating clinic consequence because it leads to dose escalation and inadequate pain control, and possibly drug dependence.
Effective pain therapies directed to preventing opioid tolerance have long been sought. The success of developing such effective therapies requires a better understanding of the underlying tolerance mechanisms. Opioid receptor internalization, down-regulation, and uncoupling from G proteins (desensitization) all have been proposed as potential mechanisms. However, no consistent changes have been identified (Nestler, 1994; Nestler et al., 1997). A phenomena called “cAMP upregulation” has been proposed as a biochemical correlation for opioid tolerance (Sharma et al., 1975; Wang et al., 1994; Nestler, 1994). This theory was expanded when linked to the regulation of protein kinase A (PKA) and CREB activation in cellular model of opioid tolerance (Nestler, 1994; Nestler, 1997). However, studies with CREB mutant mice suggested that CREB may be a factor more important for opioid dependence (Maldonado et al., 1996; Blendy et al., 1998). Inhibition of PKA has produced an inconsistent effect on behavioral manifestations of opioid tolerance (e.g., Narita et al., 1995; Bilsky et al., 1996; Shen et al., 2000).
Other studies found that blocking NMDA receptor antagonists could prevent the development of, or disrupt established, opioid tolerance (Trujillo et al., 1991; Mao et al., 1995). Central to these findings is increased intracellular Ca2+ levels resulting from NMDA receptor activation and other neuronal activation. Calcium ion (Ca2+) is used as a second messenger in neurons, leading to the activation various protein kinases, among them, Ca2+/phospholipids-dependent protein kinase (PKC) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). PKC has been implicated in opioid tolerance (Coderre et al., 1994; Mao et al., 1995; Granados-Soto et al., 2000; Narita et al., 2001). Mice lacking PKC exhibited significantly reduced opioid tolerance (Zeitz et al., 2001). NMDA receptors are known to interact with CaMKII by Ca2+ influx and phosphorylation. It is unclear from these studies, however, whether CaMKII plays a role in the development and/or maintenance of opioid tolerance.
The available opiate and opioid analgesics are derivatives of five chemical groups (i.e., phenanthrenes, phenylheptylamines, phenylpiperidines, morphinans, and benzomorphans). Pharmacologically, these opiates and nonopiates differ significantly in activity. Some are strong agonists (morphine), while others are moderate-to-mild agonists (codeine). In contrast, some opiate derivatives exhibit mixed agonist-antagonist activity (nalbuphine), whereas others are opiate antagonists (naloxone). Morphine is the prototype of the opiate and opioid analgesics, all of which have similar actions on the central nervous system.
Morphine is an alkaloid chemically derived from opium papaver somniferum. Other drugs, such as heroin, are processed from morphine or codeine. Such opiates have been used both medically and nonmedically for centuries. By the early 19th century, morphine had been extracted in a pure form suitable for solution. With the introduction of the hypodermic needle, injection of a morphine solution became the common method of administration. Of the twenty alkaloids contained in opium, only codeine and morphine are still in widespread clinical use.
The opiates are among the most powerfully acting and clinically useful drugs producing depression of the central nervous system. Drugs of this group are used principally as analgesics, but possess numerous other useful properties. Morphine, for example, is used to relieve pain, induce sleep in the presence of pain, check diarrhea, suppress cough, ease dyspnea, and facilitate anesthesia.
However, morphine also depresses respiration; increases the activity and tone of the smooth muscles of the gastrointestinal, biliary, and urinary tracts causing constipation, gallbladder spasm, and urinary retention; causes nausea and vomiting in some individuals; and can induce cutaneous pruritus. In addition, morphine and related compounds have other properties that tend to limit their usefulness.
For example, when morphine and related compounds are administered over a long time period, tolerance to the analgesic effect develops, and the dose then must be increased periodically to obtain equivalent pain relief. Eventually, tolerance and physical dependence develop, which, combined with euphoria, result in excessive use and addiction of those patients having susceptible personalities. For these reasons, morphine and its derivatives must be used only as directed by a physician (i.e., not in greater dose, more often, or longer than prescribed), and should not be used to treat pain when a different analgesic will suffice.
Nevertheless, morphine remains the major drug for the treatment of moderate to severe pain (Foley, 1993). Opioids particularly are used to treat chronic painful conditions lacking a standard treatment, such as cancer pain, posttraumatic pain, postoperative pain, and neuropathic pain. However, opioid painkillers have significant adverse side effects like respiratory depression, nausea, vomiting, dizziness, sedation, mental clouding, constipation, urinary retention, and severe itching.
These adverse side effects limit the usefulness of opioids, like morphine, as painkillers. Therefore, several companies are developing a new generation of opioid painkillers, but advances in neuroscience have not progressed a sufficient extent to provide a significant breakthrough. Typically, companies are using proprietary technology to reformulate opioid drugs, such as morphine, into branded painkillers with improved clinical benefits. To date, innovations in the field of opioid painkillers have largely focused on increasing the convenience of opioid drugs. For example, important advances have been made in opioid delivery, such as sustained release formulations and transmucosal delivery.
CaMKII is a multifunctional calcium and calumodulin activated kinase, whose α and β isoforms are abundant in the central nervous system. A vast amount of information is available for the interaction of CaMKII α isoform and NMDA receptor in longterm potentiation in hippocampal neurons, which is critical for learning and memory (e.g., Mayford et al., 1996). Glutamate can activate CaMKII through NMDA receptor and Ca2+ influx in cultured rat hippocampal neurons (Fukunaga et al., 1992). Calcium influx via NMDA receptors results in activation and Thr286 autophosphorylation of CaMKII (Strack et al., 1998; Strack et al., 2000). On the other hand, CaMKII phosphorylates and activates the NMDA receptor, and enhances Ca2+ influx through the channel (Kitamura et al., 1993).
No direct information exists for the role of CaMKII or NMDA/CaMKII interaction in opioid tolerance. Indirectly, chronic opioid administration increases both the level (Lou et al., 1999) and activity (Nehmad et al., 1982) of calmodulin, as well as calmodulin mRNA levels (Niu et al., 2000). Cytosolic free Ca2+ also can be increased after treatment with opioids (Fields et al., 1997; Quillan et al., 2002). CaMKII also has been shown to phosphorylate and activate the cAMP response element binding protein (CREB) (Hokota et al., 2001). More direct evidence arose from the finding that CaMKII and μ opioid receptor (μOR) are colocalized in the superficial layers of the spinal cord dorsal horn, an area critical for pain transmission (Bruggemann et al., 2000). The cloned pOR contains several consensus sites for phosphorylation by CaMKII (Mestek et al., 1995). Desensitization of μOR was enhanced when CaMKII was overexpressed (Mestek et al., 1995; Koch et al., 1997). Recently, hippocampal, but not striatal, CaMKII was found to modulate opioid tolerance and dependence by affecting memory pathways (Fan et al., 1999; Lou et al., 1999). The role of spinal CaMKII in opioid tolerance is unknown.
The present invention is directed to the discovery that some pharmacological actions of morphine can be modified by coadministration of an inhibitor of CaMKII, hereafter termed a “CaMKII inhibitor.”